Development of new diagnostic methods for atrial fibrillation based on miR-30d as a baiomarker

• Project/Area Number: 16K08498
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General physiology
• Research Institution: Oita University
• Principal Investigator: Ono Katsushige 大分大学, 医学部, 教授 (40253778)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 心房細動 / リモデリング / IKACh / miR-30d / イオンチャネル / アセチルコリン感受性 / conventional PKC / アセチルコリン感受性Kチャネル / Ca2+依存性プロテインキナーゼC / 心房筋 / KAChチャネル / カルシウム過負荷 / マイクロRNA

Outline of Final Research Achievements

In cardiomyocytes derived atrial fibrillation, MiR-30d was significantly upregulated in cardiomyocytes from AF patients, whereas the mRNA and protein levels of CACNA1C/Cav1.2 and KCNJ3/Kir3.1, postulated targets of miR-30d, were markedly reduced. KCNJ3/Kir3.1 expression was downregulated by transfection of the miR-30 precursor, concomitant with a reduction of the acetylcholine-sensitive inward-rectifier K+ current (IK.ACh). KCNJ3/Kir3.1 (but not CACNA1C/Cav1.2) expression was enhanced by the knockdown of miR-30d. The Ca2+ ionophore, A23187, induced a dose-dependent upregulation of miR-30d, followed by the suppression of KCNJ3 mRNA expression. Blockade of protein kinase C signaling blunted the [Ca2+]i-dependent downregulation of Kir3.1 via miR-30d.

Academic Significance and Societal Importance of the Research Achievements

不整脈の発生と維持には様々な因子が介在する。心房細動の発症には肺静脈心筋の自動能が関わり、その維持には心房筋の線維化と電気的性質の変性が関与する。本研究ではmicroRNA30d (miR-30d)のカリウムチャネルのへの転写後制御がそのリモデリングの背景に位置することを明らかにしたものであり、またこのmiR-30dの発現増加には心筋細胞内のカルシウム(Ca)過負荷が原因であることも明らかにした。心房細動は高齢者に多発し、70歳以上では７人に1人が罹患する。その心房細動の発症とその予防に対してTargetとなる分子を見いだしたことは社会的に大きな意義を持つと言える。

Research Products

• [Journal Article] Magnesium Deficiency Causes Transcriptional Down-Regulation of Kir2.1 and Kv4.2Channels in Cardiomyocytes Resulting in QT interval Prolongation (2020)
  • Author(s): Shimaoka T, Wang Y, Morishima M, Miyamoto S, Ono K
  • Journal Title: Circulation Journal Volume: 6 Pages: 211-215
  • NAID: 130007879308
  • Peer Reviewed / Open Access
• [Journal Article] Cardiacspecific transcription factor Csx/Nkx2.5 regulates transient-outward K+channel expression in pluripotent P19 cell-derived cardiomyocytes (2020)
  • Author(s): Uchino T, Zheng M, Wang Y, Ono K
  • Journal Title: J Physiol Sci Volume: 7 Issue: 1 Pages: 1-7
  • DOI: 10.1186/s12576-020-00748-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Short- and long-term roles of phosphatidylinositol 4,5-bisphosphate PIP2 on Cav3.1- and Cav3.2-T-type calcium channel current (2019)
  • Author(s): Liu Yangong、Iwano Tomohiro、Ma Fangfang、Wang Pu、Wang Yan、Zheng Mingqi、Liu Gang、Ono Katsushige
  • Journal Title: Pathophysiology Volume: 26 Issue: 1 Pages: 31-38
  • DOI: 10.1016/j.pathophys.2018.12.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Asparagine-linked glycosylation modifies voltage-dependent gating properties of CaV3.1-T-type Ca2+ channel (2019)
  • Author(s): Liu Yangong、Wang Pu、Ma Fangfang、Zheng Mingqi、Liu Gang、Kume Shinichiro、Kurokawa Tatsuki、Ono Katsushige
  • Journal Title: The Journal of Physiological Sciences Volume: 69 Issue: 2 Pages: 335-343
  • DOI: 10.1007/s12576-018-0650-4
  • Peer Reviewed
• [Journal Article] Testosterone-mediated upregulation of delayed rectifier potassium channel in cardiomyocytes causes abbreviation of QT intervals in rats. (2018)
  • Author(s): Masuda K, Takanari H, Morishima M, Ma F, Wang Y, Takahashi N, Ono K.
  • Journal Title: J Physiol Sci Volume: Jan 13 Issue: 6 Pages: 1-9
  • DOI: 10.1007/s12576-017-0590-4
  • NAID: 40021720520
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Atrial Fibrillation-Mediated Upregulation of miR-30d Regulates Myocardial Electrical Remodeling of the G-Protein-Gated K⁺ Channel, <i>I</i>_K.ACh (2016)
  • Author(s): Morishima M, Iwata E, Nakada C, Tsukamoto Y, Takanari H, Miyamoto S, Moriyama M, Ono K
  • Journal Title: Circulation Journal Volume: 80 Issue: 6 Pages: 1346-1355
  • DOI: 10.1253/circj.CJ-15-1276
  • NAID: 130005153582
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access